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The synthetic vitamin A derivative, fenretinide (4HPR) was developed in the 1970’s as a means to induce retinoid cancer preventive effects in cells and tissues devoid of the retinoic acid receptor, and has become an important compound for chemoprevention of a variety of cancers such as oral squamous cell carcinoma (OSCC). However, OSCC chemoprevention clinical trials with orally delivered 4HPR have been unsuccessful likely due to extensive first pass metabolism, systemic toxicity, and sub-therapeutic levels of 4HPR at the target site. Local 4HPR delivery vehicles have the potential to deliver therapeutic doses while alleviating any systemic side effects. Limited penetration distance of the drug in tissues, however, is one of the most prevalent challenges with the local delivery approach. To overcome these limitations and to increase drug exposure at the site of action, solubilizers and permeation enhancers were combined with 4HPR in local delivery depots, and their drug release kinetics in vivo and 4HPR’s tissue uptake in presence of solubilizers ex vivo were evaluated. Long-acting release of 4HPR from injectable millicylindrical implants were prepared with poly(lactic-co-glycolic acid) and polyvinyl alcohol (PVA)/sucrose matrices as a function of drug loading and the presence of various excipients to enhance the release of the water-insoluble 4HPR. 4HPR was released from PLGA implants much slower in vivo than in the Tween 80-solubilizing media in vitro, with a 3-week lag phase followed by continuous release of >2 months, and showed some release enhancement by addition of solubilizers. The water-soluble PVA/sucrose implant provided continuous drug release for up to 6 weeks in vivo. These 4HPR-PLGA formulations were further evaluated in an oral cancer xenograph mouse model, and shown to be effective at reducing rate of tumor growth over 10 days. A remarkable solubility enhancing formulation was achieved with 4HPR amorphous solid dispersions (ASDs) prepared with polvinylpyrrolidone (PVP) polymer. The PVP-4HPR ASD was loaded into PLGA implants and evaluated in vivo, and found to substantially improve release kinetics from previous crystalline 4HPR formulations. Tissue binding kinetics was characterized in buccal epithelia and subcutaneous tissues in presence of various solubilizing and permeation enhancing media. Time of exposure, but not solubilizer or permeation enhancers, affected uptake and 4HPR exhibited a five-fold greater binding affinity to buccal epithelia relative to subcutaneous connective tissues. These optimized long-acting 4HPR millicylindrical implants were further evaluated in vivo over 2 weeks in rabbit buccal epithelia, for their ability to enhance drug-tissue distribution. Quantitative Raman spectroscopic imaging was utilized to measure drug-tissue concentration gradients in excised tissue sections. The implants released much faster in the mouth compared to our previous studies in s.c. tissue, and the drug penetration in the buccal tissues (i.e. distance to reach 10% of concentration at implant surface, or C10) was on the order of 0.5- 8 mm for all formulations. The ASD of 4HPR in PLGA provided the greatest drug penetration through tissues, likely as a result of supersaturated drug concentrations next to the implant. Hence, these approaches may be useful for local delivery of 4HPR and OSCC chemoprevention.